Oxidative stress in the pathology and treatment of systemic lupus erythematosus

Key Points

  • Oxidative stress—generated through multiple mechanisms in a cell-type-specific manner—is a substantial contributor to disease pathogenesis, organ damage and comorbidities in patients with systemic lupus erythematosus (SLE)

  • Pathways of oxidative pathogenesis, such as oxidative modification of self antigens and T-cell dysfunction, have been identified

  • Organ systems in which the clinical importance of oxidative damage in SLE has been recognized include the cardiovascular and renal systems and the skin

  • Biomarkers of oxidative stress correlate directly with disease activity in SLE

  • Depletion of glutathione (reflecting oxidative stress) might have a pathogenic role; its reversal by N-acetylcysteine seems to have therapeutic benefit in mouse models and patients with SLE

Abstract

Oxidative stress is increased in systemic lupus erythematosus (SLE), and it contributes to immune system dysregulation, abnormal activation and processing of cell-death signals, autoantibody production and fatal comorbidities. Mitochondrial dysfunction in T cells promotes the release of highly diffusible inflammatory lipid hydroperoxides, which spread oxidative stress to other intracellular organelles and through the bloodstream. Oxidative modification of self antigens triggers autoimmunity, and the degree of such modification of serum proteins shows striking correlation with disease activity and organ damage in SLE. In T cells from patients with SLE and animal models of the disease, glutathione, the main intracellular antioxidant, is depleted and serine/threonine-protein kinase mTOR undergoes redox-dependent activation. In turn, reversal of glutathione depletion by application of its amino acid precursor, N-acetylcysteine, improves disease activity in lupus-prone mice; pilot studies in patients with SLE have yielded positive results that warrant further research. Blocking mTOR activation in T cells could conceivably provide a well-tolerated and inexpensive alternative approach to B-cell blockade and traditional immunosuppressive treatments. Nevertheless, compartmentalized oxidative stress in self-reactive T cells, B cells and phagocytic cells might serve to limit autoimmunity and its inhibition could be detrimental. Antioxidant therapy might also be useful in ameliorating damage caused by other treatments. This Review thus seeks to critically evaluate the complexity of oxidative stress and its relevance to the pathogenesis and treatment of SLE.

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Figure 1: Mitochondrial generation and systemic propagation of oxidative stress, and overview of redox balance mechanisms.
Figure 2: Overview of molecular pathways of oxidative stress and potential points of intervention in T cells in SLE.
Figure 3: Molecular targets of oxidative stress in T-cell signal transduction.
Figure 4: Consequences of compartmentalized oxidative stress in T cells and phagocytic cells for the proinflammatory intercellular signalling network in SLE.

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Acknowledgements

This work was supported in part by grants AI 048,079, AI 072,648, and AT004332 from the National Institutes of Health, the Alliance for Lupus Research, and the Central New York Community Foundation. The author is grateful to Mariana Kaplan (University of Michigan) and Mark Shlomchik (University of Pittsburgh) for helpful discussions and to Paul Phillips (State University of New York) for continued encouragement and support. Due to space limitations, important discoveries of oxidative stress research in SLE may have only been referenced through reviews.

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Perl, A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol 9, 674–686 (2013). https://doi.org/10.1038/nrrheum.2013.147

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